This invention is directed to a method for stereoselective xcex1-substitution of unprotected xcex2-amino ester compounds under mild conditions. The resultant xcex1-substituted unprotected xcex2-amino ester compounds are useful in preparing a plethora of biologically active compounds, for example, Factor Xa inhibitors that are useful for treating physiological conditions in a patient that can be ameliorated by administering the inhibitor of Factor Xa.
Current methods for xcex1-substitution of xcex2-amino ester or acid compounds require the amine to be protected/functionalized before the substitution. In addition, current methods also necessitate the eventual removal of the amine protecting/functionalization group.
Juaristi et al., J. Org. Chem., 58, 2282-5 (1993) disclose the xcex1-substitution of xcex2-amino acid compounds as follows in Scheme I: (1) converting the xcex2-amino acid compounds 
to corresponding perhydropyrimidine-4-one compounds; (2) alkylating the perhydropyrimidine-4-one compounds; and (3) ring opening the resultant alkylated perhydropyrimidine-4-one compounds to yield the corresponding xcex1-alkylated xcex2-amino acid compounds. See Jurasti, Enantio-selective Synthesis of xcex2-amino Acids (Wiley-VCH, New York, 1997) 263-70. Juaristi et al. do not disclose the xcex1-substitution of unprotected or unfunctionalized xcex2-amino acid compounds.
Seebach et al., Tetrahedron Lett., 28(7), 3103-6 (1987) disclose the xcex1-substitution of xcex2-amino ester compounds as follows in Scheme II: (1) protecting the amine group of the xcex2-amino ester compounds; (2) alkylating the N-protected xcex2-amino ester compounds; and (3) deprotecting the xcex1-alkylated N-protected xcex2-amino acid com-pounds. See also Estermann et al., Helv. Chim. Acta, 71, 1824-39 (1988). Neither Seebach or Estermann disclose xcex1-substitution of unprotected or unfunctionalized xcex2-amino acid compounds. 
In view of the aforesaid, it would be worthwhile to have synthetic procedures for preparing xcex1-substituted xcex2-amino ester compounds that require fewer reactants and/or steps, i.e., simplified and less costly synthetic procedures.
The present invention is directed to a method for stereoselective substitution in which a (mono or un)-xcex1-substituted unprotected xcex2-amino ester compound or salt thereof is reacted with an aliphatic electrophile in the presence of a base selected from alkyl lithium compounds, lithium hydride, lithium amide, lithium dialkyl amides and alkali hexamethyldisilylamines.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid protecting groupxe2x80x9d means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and preferably to be selectively removable. The use of acid protecting groups is well known in the art for protecting against undesirable reactions during a synthetic procedure and many such protecting groups are known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields. (See U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are incorporated herein by reference, and T. W. Green and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.) Examples of carboxylic acid protecting groups include esters such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, dialkylaminoalkyl (e.g., dimethylaminoethyl and the like), trimethylsilyl, and the like, and amides and hydrazides including N,N-dimethyl, 7-nitroindolyl, hydrazide, N-pbenyl-bydrazide, C1 to C8 loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; alkanoyloxy-alkyl groups such as pivaloyloxymethyl or propionyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxy-carbonylmethyl and the like; alkoxycarbonyloxyalkyl, such as t-butyloxycarbon-yloxymethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxy-alkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylamino-carbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl) alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
xe2x80x9cAmine protecting groupxe2x80x9d means an easily removable group known in the art to protect an amino group against undesirable reaction during synthetic procedures and preferably selectively removable. The use of amine protecting groups is well known in the art for protecting against undesirable reactions during a synthetic procedure and many such protecting groups are known (see, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991)). Preferred protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, benz-oyl, aminocaproyl, and the like, and acyloxy including methoxy-carbonyl, 9-fluorenylmethoxy-carbonyl, 2,2,2-tri-fluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-di-methylpropynyloxycarbonyl, benzyloxy-carbonyl (CBZ), p-nitrobenzyloxycarbony, 2,4-di-chlorobenzyloxy-carbonyl, and the like.
xe2x80x9cAcid labile amine protecting groupxe2x80x9d means an amine protecting group as defined above which is readily removed by treatment with acid while remaining relatively stable to other reagents. A preferred acid labile amine protecting group is tert-butoxycarbonyl (BOC).
xe2x80x9cHydrogenation labile amine protecting groupxe2x80x9d means an amine protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile protecting group is benzyloxycarbonyl (CBZ).
xe2x80x9cHydrogenation labile acid protecting groupxe2x80x9d means an acid protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile acid protecting group is benzyl.
xe2x80x9cThiol protecting groupxe2x80x9d means a protecting group that is readily removed by some reagents while being relatively stable to other reagents. The use of thiol protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. Exemplary thiol protecting groups are trityl (Trt), acetamidomethyl (Acm), and the like.
xe2x80x9cHydroxy protecting groupxe2x80x9d means a protecting group that is readily removed by some reagents while being relatively stable to other reagents. The use of hydroxy protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. Exemplary hydroxy protecting groups are t-butyl, benzyl, tetrahydropyranyl, and the like.
xe2x80x9cAliphaticxe2x80x9d means a radical derived from a non aromatic Cxe2x80x94H bond by removal of the hydrogen atom. Additional aliphatic or aromatic radicals as defined herein may further substitute the aliphatic radical. Representative aliphatic groups include alkyl, alkenyl, alkynyl, cyclo-alkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkyloxyalkyl, aralkyloxycarbon-ylalkyl, aralkyl, aralkynyl, aralkyloxyalkenyl, heteroaralkenyl, heteroaralkyl, heteroaralkyloxy-alkenyl, heteroaralkyloxyalkyl, heteroaralkynyl, fused arylcycloalkyl, fused heteroarylcyclo-alkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, and the like.
xe2x80x9cAliphatic electrophilexe2x80x9d means an aliphatic compound subject to nucleophilic substitu-tion. Representative aliphatic electrophiles include (Br, 1, or (aryl or alkyl) sulfonate) aliphatic compounds (R6aXxe2x80x2 or R6bXxe2x80x2, wherein R6a and R6b are aliphatic and Xxe2x80x2 is Br, I, arylsulfonate or alkylsulfonate). Preferred aliphatic compounds subject to nucleophilic substitution are primary or secondary alkyl, alkynyl, allylic or benzylic compounds, such as methyl iodide, propen-1-yl bromide or m-cyanobenzyl bromide. Preferred aliphatic electrophiles also include benzalde-hyde, benzyl chloride and phenylchloroformate.
xe2x80x9cAromaticxe2x80x9d means a radical derived from an aromatic Cxe2x80x94H bond by removal of the hydrogen atom. Aromatic includes both aryl and heteroaryl rings as defined herein. Additional aliphatic or aromatic radicals; as defined herein may further substitute the aryl or heteroaryl ring. Representative aromatic groups include aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cyclo-alkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, and the like.
xe2x80x9cAlkenylxe2x80x9d means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbonxe2x80x94carbon double bond. Preferred alkenyl groups have 2 to about 12 carbon atoms; more preferred alkenyl groups have 2 to about 4 carbon atoms. The alkenyl group is optionally substituted with one or more alkyl group substituents as defined herein. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenyloxyxe2x80x9d means an alkenyl-O-group wherein the alkenyl group is as herein described. Representative alkenyloxy groups include allyloxy or 3-butenyloxy.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-O-group wherein the alkyl group is as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy, and the like.
xe2x80x9cAlkoxyalkylenylxe2x80x9d means an alkyl-O-alkyl-group wherein alkyl and alkyl are as defined herein. Representative alkoxyalkylenyl groups include methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl.
xe2x80x9cAlkoxyalkoxyxe2x80x9d means an alkyl-O-alkyl-O-group. Representative alkoxyalkoxy include methoxymethoxy, methoxyethoxy, ethoxyethoxy, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an ester group; i.e. an alkyl-Oxe2x80x94CO-group wherein alkyl is as defined herein. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxy-carbonyl, t-butyloxycarbonyl, and the like.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group that may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means about 1 to about 4 carbon atoms in the chain that may be straight or branched. The alkyl may be substituted with one or more xe2x80x9calkyl group substituentsxe2x80x9d which may be the same or different, and include halo, cyclo-alkyl, alkoxy, alkoxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl. Representa-tive alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, and methoxyethyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-S-group wherein the alkyl group is as defined herein. Preferred alkylthio groups are those wherein the alkyl group is lower alkyl. Representative alkylthio groups include methylthio, ethylthio, i-propylthio, heptylthio, and the like.
xe2x80x9cAlkynylxe2x80x9d means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms that contains at least one carbonxe2x80x94carbon triple bond. Preferred alkynyl groups have 2 to about 12 carbon atoms. More preferred alkynyl groups contain 2 to about 4 carbon atoms. xe2x80x9cLower alkynylxe2x80x9d means alkynyl of 2 to about 4 carbon atoms. The alkynyl group may be substituted by one or more alkyl group substituents as defined herein. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.
xe2x80x9cAlkynyloxyxe2x80x9d means an alkynyl-O-group wherein the alkynyl group is defined herein. Representative alkynyloxy groups include propynyloxy, 3-butynyloxy, and the like.
xe2x80x9cAlkynyloxyalkylxe2x80x9d means alkynyl-O-alkyl-group wherein alkynyl and alkyl are defined herein.
xe2x80x9cAminoxe2x80x9d means a group of formula Y1Y2Nxe2x80x94 wherein Y1 and Y2 are independently hydrogen; or alkyl. Representative amino groups include amino (H2Nxe2x80x94), methylamino, dimethylamino, diethylamino, and the like.
xe2x80x9cAminoalkylxe2x80x9d means an amino-alkyl-group wherein amino and alkyl are defined herein. Representative aminoalkyl groups include dimethylaminomethyl, and the like.
xe2x80x9cAralkenylxe2x80x9d means an aryl-alkenyl group wherein aryl and alkenyl are define herein. Preferred aralkenyls contain a lower alkenyl moiety. A representative aralkenyl group is 2-phenethenyl.
xe2x80x9cAralkyloxyxe2x80x9d means an aralkyl-Oxe2x80x94 group wherein aralkyl is defined herein. Representative aralkoxy groups include benzyloxy, naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.
xe2x80x9cAralkyloxyalkylxe2x80x9d means an aralkyl-O-alkyl-group wherein aralkyl and alkyl are defined herein. A representative aralkoxyalkyl group is benzyloxyethyl.
xe2x80x9cAralkyloxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94COxe2x80x94 group wherein aralkyl is defined herein. A representative aralkoxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cAralkyloxycarbonylalkylxe2x80x9d means an aralkoxycarbonyl-alkyl-group wherein aralkoxycarbonyl and alkylene are defined herein. Representative aralkoxycarbonylalkyls include benzyloxycarbonylmethyl, benzyloxycarbonylethyl.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl-group wherein aryl and alkyl are defined herein. Preferred aralkyls contain a lower alkylene group. Representative aralkyl groups include benzyl, 2-phenethyl, naphthlenemethyl, and the like.
xe2x80x9cAralkyloxyalkenylxe2x80x9d means an aralkyl-O-alkenyl-group wherein aralkyl and alkenyl are defined herein. A representative aralkyloxyalkenyl group is 3-benzyloxyallyl.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-S group wherein aralkyl is defined herein. A represent-ative aralkylthio group is benzylthio.
xe2x80x9cArylxe2x80x9d means an aromatic mono- or multicyclic ring system of 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative aryl groups include phenyl and naphthyl.
xe2x80x9cAralkynylxe2x80x9d means an aryl-alkynylene-group wherein aryl and alkynyl are defined herein. Representative aralkynyl groups include phenylacetylenyl and 3-phenylbut-2-ynyl.
xe2x80x9cAryldiazoxe2x80x9d means an aryl-Nxe2x95x90Nxe2x80x94 group wherein aryl is defined herein. Representative aryldiazo groups include phenyldiazo and naphthyldiazo.
xe2x80x9cArylcarbamoylxe2x80x9d means an aryl-NHCOxe2x80x94 group, wherein aryl is defined herein. xe2x80x9cCarbamylxe2x80x9d means a group of formula Y1Y2NCOxe2x80x94 wherein Y1 and Y2 are as defined herein. Representative carbamyl groups include carbamoyl (H2NCOxe2x80x94)dimethylcarbamoyl (Me2NCOxe2x80x94), and the like.
xe2x80x9cFused arylcycloalkenylxe2x80x9d means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the cycloalkenyl portion. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkenyl include 1,2-dihydronaphthylene, indene, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylarylxe2x80x9d means a radical derived from a fused arylcycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Representative fused cycloalkenylaryl are as described herein for a fused arylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylcycloalkylxe2x80x9d means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkyl includes 1,2,3,4-tetrahydronaphthyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylarylxe2x80x9d means a radical derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused cycloalkyl-aryl groups are as described herein for a fused arylcycloalkyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclenylxe2x80x9d means a radical derived from a fused aryl and heterocyclen-yl as defined herein by removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused arylheterocyclenyls are those wherein aryl is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl portion of the fused arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heterocyclenyl portion of the fused arylheterocyclenyl is optionally oxidized to the corresponding N-oxide. Representative fused arylheterocyclenyl include 3H-indolinyl, 1H-2-oxoquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, 1,2-dihydro-isoquinolinyl, 3,4-dihydroisoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclenylarylxe2x80x9d means a radical derived from a fused arylheterocyclenyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused heterocyclenylaryl are as defined herein for a fused arylheterocyclenyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclylxe2x80x9d means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused arylheterocyclyls are those wherein aryl is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylhetero-cyclyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heterocyclyl portion of the fused arylheterocyclyl is optionally oxidized to the corresponding N-oxide. Representative preferred fused arylheterocyclyl ring systems include indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenz[f]isoindolyl, 1,2,3,4-tetra-hydrobenz[g]isoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclylarylxe2x80x9d means a radical derived from a fused aryheterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl ring systems are as described for fused arylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cCarboxyxe2x80x9d means a HO(O)C-group (i.e. a carboxylic acid).
xe2x80x9cCycloalkyloxyxe2x80x9d means a cycloalkyl-Oxe2x80x94 group wherein cycloalkyl is defined herein. Representative cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Rep-resentative monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms which contains at least one carbonxe2x80x94carbon double bond. Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is norbornylenyl.
xe2x80x9cDiazoxe2x80x9d means a bivalent xe2x80x94Nxe2x95x90Nxe2x80x94 radical; xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo.
xe2x80x9cHeteroaralkenylxe2x80x9d means a heteroaryl-alkenyl-group wherein heteroaryl and alkenyl are defined herein. Preferred heteroaralkenyls contain a lower alkenylene moiety. Representa-tive heteroaralkenyl groups include 4-pyridylvinyl, thienylethenyl, pyridylethenyl, imidazolyl-ethenyl, pyrazinylethenyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a heteroaryl-alkylenyl-group wherein heteroaryl and alkylenyl are defined herein. Preferred heteroaralkyls contain a lower alkylenyl group. Representative heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like.
xe2x80x9cHeteroaralkyloxyxe2x80x9d means an heteroaralkyl-Oxe2x80x94 group wherein heteroaralkyl is defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxy.
xe2x80x9cHeteroaralkyloxyalkenylxe2x80x9d means a heteroaralkyl-O-alkenyl-group wherein heteroaralkyl and alkenyl are defined herein. A representative heteroaralkyloxyalkenyl group is 4-pyridylmethyloxyallyl.
xe2x80x9cHeteroaralkyloxyalkylxe2x80x9d means a heteroaralkyl-O-alkyl-group where heteroaralkyl and alkyl are defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxyethyl.
xe2x80x9cHeteroaralkynylxe2x80x9d means a heteroaryl-alkynyl-group where heteroaryl and alkynylene are defined herein. Preferred heteroaralkynyls contain a lower alkynyl moiety. Representative heteroaralkynyl groups include pyrid-3-ylacetylenyl, quinolin-3-ylacetylenyl, 4-pyridylethynyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. The xe2x80x9cheteroarylxe2x80x9d may also be substituted by one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A nitrogen atom of a heteroaryl may be oxidized to the corresponding N-oxide. Representative heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azain-dolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thieno-pyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl and 1,2,4-triazinyl.
xe2x80x9cHeteroaryldiazoxe2x80x9d means a heteroaryl xe2x80x94Nxe2x95x90Nxe2x80x94 where heteroaryl is as defined herein.
xe2x80x9cFused heteroarylcycloalkenylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion. In preferred fused heteroarylcycloalkenyls the heteroaryl and the cycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroaryl-cycloalkenyl is optionally substituted by one or more ring system substituents, as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquin-azo 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylheteroarylxe2x80x9d means a radical derived from a fused heteroaryl-cycloalkenyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkenylheteroaryl are as described herein for fused heteroaryl-cycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylcycloalkylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. In preferred fused heteroarylcycloalkyls the heteroaryl and the cycloalkyl each consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitro-gen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcyclo-alkyl is optionally substituted by one or more ring system substituents, as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyl include 5,6,7,8-tetra-hydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetra-hydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylheteroarylxe2x80x9d means a radical derived from a fused heteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as described herein for fused heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylheterocyclenylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heterocyclenyl portion. In preferred fused heteroarylheterocyclenyls the heteroaryl and the heterocyclenyl each consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heter-ocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted by one or more ring system substituents, as defined herein. The nitrogen atom of the heteroaryl portion of the fused hetero-arylheterocyclenyl is optionally oxidized to the corresponding N-oxide. The nitrogen atom of the heterocyclenyl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylheterocyclenyl include 7,8-dihydro [1,7]naphthyridinyl, 1,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl, 1,2-dihydro-1,7-naphthyridin-yl, 1,2-dihydro-1,8-naphthyridinyl, 1,2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to the parent moiety is through a non aromatic carbon atom.
xe2x80x9cFused heterocyclenylheteroarylxe2x80x9d means a radical derived from a fused heteroaryl-heterocyclenyl as defined herein by the removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclenylheteroaryl are as described herein for fused heteroarylheterocyclenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylheterocyclylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heterocyclyl portion. In preferred fused heteroarylheterocyclyls the heteroaryl and the heterocyclyl each consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylheterocyclyl is optionally substituted by one or more ring system substituents, as defined herein. The nitrogen atom of either the heteroaryl or the heterocyclyl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide. Representative fused hetero-arylheterocyclyl include 2,3-di-hydro-1H pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl, 1,2,3,4-tetrahydro[b][1,6]naphthyridin-2-yl 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl, 2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepino[4,5-b]indole-2 yl, 5,6,7,8-tetrahydro[1,7]napthyridinyl, 1,2,3,4-tetrhydro[2,7]naphthyridyl, 3,4-dihydro-2H-1-oxa-[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, 1,2,3,4-tetrahydro[1,5]naptbyridinyl, 1,2,3,4-tetrahydro[1,6]napthyridinyl, 1,2,3,4-tetrahydro[1,7]napthyridinyl, 1,2,3,4-tetrahydro[1,8]napth-yridinyl, 1,2,3,4tetrahydro[2,6]napthyridinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclylheteroarylxe2x80x9d means a radical derived from a fused heteroaryl-heterocyclyl as defined herein, by removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclylheteroaryl are as described herein for fused heteroaryl-heterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cHeterocyclenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 12 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system are elements other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbonxe2x80x94carbon double bond or carbon-nitrogen double bond. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The heterocyclenyl may be optionally substituted by one or more ring system substituents, as defined herein. The atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide. Representative monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydro-pyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrapyrazolinyl, and the like. Representative oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like
xe2x80x9cHeterocyclylxe2x80x9d means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respective-ly is present as a ring atom. The heterocyclyl is optionally substituted by one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. The atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide. Representative mono-cyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorph-olinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a heterocyclyl-alkyl group wherein heterocyclyl and alkyl are defined herein. Preferred heterocyclylalkyls contain a lower alkyl moiety. A representative heteroaralkyl group is tetrahydropyranylmethyl.
xe2x80x9cHeterocyclylalkyloxyalkylxe2x80x9d means a heterocyclylalkyl-O-alkyl group wherein heterocyclylalkyl and alkyl are defined herein. A representative heterocyclylalkyloxyalkyl group is tetrahydropyranylmethyloxymethyl.
xe2x80x9cHeterocyclyloxyxe2x80x9d means a heterocyclyl-Oxe2x80x94 group wherein heterocyclyl is defined here-in. Representative heterocyclyloxy groups include quinuclidyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy, 7-oxa-bicyclo[2.2.1]heptanyloxy, hydroxytetrahydropyranyloxy, hydroxy-7-oxabicyclo[2.2.1]heptan-yloxy, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl group as defined herein substituted with one or more hydroxy groups. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cN-oxidexe2x80x9d means a 
group.
xe2x80x9cPhenoxyxe2x80x9d means a phenyl-Oxe2x80x94 group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPhenylthioxe2x80x9d means a phenyl-Sxe2x80x94 group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPyridyloxyxe2x80x9d means a pyridyl-O-group wherein the pyridyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cRing system substituentxe2x80x9d means a substituent attached which optionally replaces hydrogen on an aromatic or non-aromatic ring system. Ring system substituents are selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, thiol, alkoxy, aryloxy, aralkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo, amino, aminoalkyl, sulfamoyl and Y1Y2NCOxe2x80x94 wherein Y1 and Y2 are as defined herein. When a ring system is saturated or partially saturated, the xe2x80x9cring system substituentxe2x80x9d further comprises methylene (H2C).
xe2x80x9cSulfamoylxe2x80x9d means a group of formula Y1Y2NSO2xe2x80x94 wherein Y1 and Y2 are as defined herein. Representative sulfamyl groups are sulfamoyl (H2NSO2xe2x80x94) and dimethylsulfamoyl (Me2NSO2xe2x80x94).
Base compounds useful according to the method of this invention are selected from alkyl lithium compounds, lithium hydride, lithium amide, lithium dialkyl amides and alkali hexamethyldisilylamines. Preferred alkyl lithium compounds include butyl lithium compounds. The preferred lithium dialkyl amide is lithium diisopropyl amide. Alkali hexamethyldisilyl-amines are more preferred, particularly LiHMDS, NaHMDS and KHMDS. The most preferred base is LiHMDS.
A preferred unprotected xcex2-amino ester compound for use as a starting material according to the invention is of the formula I wherein R1 and R2 are independently hydrogen, aliphatic or aromatic; R3, R4 and R5 are independently aliphatic or aromatic; and R6a and R6b are independently hydrogen, aliphatic or aromatic, provided that one of R6a and R6b is hydrogen, or a salt thereof. 
When R3 is methyl, the base compound is preferably an alkali hexamethyldisilylamine.
A more preferred xcex2-amino ester compound for use as a starting material according to the invention is of the formula II 
wherein at least one of R1, R2 and R5 is hydrogen; R3 and R4 are independently aliphatic or aromatic; and R6a and R6b are hydrogen, or a salt thereof.
In one preferred compound of formula II, R1 and R2 are both hydrogen. In another preferred compound of formula II, R3 is alkyl or arylalkyl, and more preferably is methyl, ethyl or benzyl. In still another one preferred compound of formula II, R4 is alkyl, and more prefer-ably is methyl. In yet another preferred compound of formula II, R5 is hydrogen.
A preferred xcex1-substituted unprotected xcex2-amino ester compound prepared according to the invention is of the formula III 
wherein R1 and R2 are independently hydrogen, aliphatic or aromatic; R3, R4 and R5 are independently aliphatic or aromatic; and one of R6a and R6b is hydrogen, aliphatic or aromatic and the other of R6a and R6b is aliphatic.
A preferred xcex1-substituted unprotected xcex2-amino ester compound prepared according to the invention is of the formula IV 
wherein R1, R2 and R5 are independently hydrogen, aliphatic or aromatic; R3 and R4 are independently aliphatic or aromatic; and one of R6a and R6b is hydrogen and the other of R6a and R6b is aliphatic.
In one preferred compound of formula IV, R1 and R2 are both hydrogen. In another preferred compound of formula IV, R3 is alkyl or arylalkyl, and more preferably is methyl, ethyl or benzyl. In still another preferred compound of formula IV, R4 is alkyl, and more preferably is methyl. In yet another preferred compound of formula IV, R5 is hydrogen. In another preferred compound of formula IV, one of R6a and R6b is hydrogen and the other of R6a and R6b is alkyl, alkenyl, aralkyl or heteroaralkyl.
According to the method of this invention the xcex1-substitution is effected preferentially anti relative to the relative stereochemical configuration of the unprotected xcex2-amino moiety in the compound of formula IV. The xcex1-substitution is effected preferably in a ratio from about 24 to 1 (anti:syn) depending on the aliphatic compound subject to nucleophilic substitution, alkali hexamethyldisilylamine base, or salt of the unprotected xcex2-amino ester used, or whether an additional lithium salt is used.
A suitable solvent for carrying out the method of the invention is an aprotic solvent. The aprotic solvent includes polar and non-polar aprotic solvents; preferably polar aprotic solvent. xe2x80x9cPolar aprotic solventxe2x80x9d means aprotic oxygen containing aliphatic selected from lower alkyl ethers, cyclic ethers and glymes, heteroaryl solvents and DMF. The solvent may also be a mixture of any of these solvents. The lower alkyl ethers are selected from diethyl ether, dibutyl ether, methyl t-butyl ether, and the like. The cyclic ethers are selected from tetrahydrofuran, tetrahydropyran, and the like. The glymes are selected from ethylene glycol dimethyl ether, ethylene glycol ethyl methyl ether, ethylene glycol methyl n-propyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, and the like. A preferred solvent according to the method of the invention is tetrahydrofuran.
The method of the invention may also be carried out in the presence of a nonpolar aprotic (hydrocarbon) solvent. The hydrocarbon solvent is a C4-15 aliphatic compound or chlorinated derivative thereof understood by those skilled in the art to be unreactive under the conditions of this invention, or C6-12 aryl compound or chlorinated derivative thereof . The C4-15 aliphatic compound is selected from the group consisting of heptane, 2-methylpropane, trans-1,2-dimethylcyclopentane, spiropentane, cis-1,4-dimethyl-cylohexane, decane, n-dodec-ane and cycloheptane. The C6-12 aryl compound is selected from the group consisting of benzene, toluene, xylene, mesitylene, tetralin, 2-ethylnaphthalene and p-cymene.
The reacting step is performed at a temperature between about xe2x88x9278xc2x0 C. to about 10xc2x0 C.; more preferably between about xe2x88x9235xc2x0 C. to about xe2x88x920xc2x0 C.; and most preferably between about xe2x88x9235xc2x0 C. to about xe2x88x9215xc2x0 C.
In a further embodiment of the invention, a Li, Na or K inorganic salt is added to the aprotic solvent. Lithium salts are preferred, particularly lithium halides, more preferably lithium bromide.
It is to be understood that this invention covers all appropriate combinations of the par-ticular and preferred groupings referred to herein. Compounds of formula I may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention herein. In carrying out the method according to the invention protic substituents such as thiol, hydroxy, carboxy or Y1Y2Nxe2x80x94 on variables R1, R2, R3, R4, R5, R5, R6a and R6b may be protected useful appropriate protecting groups as described herein that are understood by those skilled in the art to be unreactive under the conditions of this invention.
It will be apparent to those skilled in the art that certain compounds that are prepared according to the invention can exhibit isomerism, i.e., geometrical isomerism, e.g., E or Z isomerism, or optical isomerism, e.g., R or S configurations. Geometrical isomers include the cis and trans forms of compounds having alkenyl or diazo moieties. Individual geometrical isomers and stereoisomers compounds prepared according to the invention, and their mixtures, are within the scope of the invention. Such isomers can be separated from their mixtures by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
Compounds of the present invention are useful in the form of the free base or acid or in the form of salts thereof. All forms are within the scope of the invention. Where the compound of the present invention is substituted with a basic moiety, acid addition salts can be formed and can be a simply more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, salts whose activity/reactivity relative to their free bases is not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for pur-poses of purification, and identification, or when it is used as inter-mediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzene-sulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, benzoic acid and the like. The corresponding acid addition salts comprise the following: hydrohalides, e.g. hydro-chloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartar-ate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-xcex2-hydroxy-naphthoates, gentisates, mesylates, isethionates, di-p-toluoyltartrates, methanesulfon-ate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinate and benzoate, respectively. A preferred acid addition salt is the benzoate.
According to the invention, acid addition salts of the inventive compounds are prepared by reaction of the free base with the appropriate acid, by known methods. For example, the acid addition salts of the inventive compounds are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or by concentration of the solution.
The free base form of compounds according to this invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.